DEFINING MECHANISMS UNDERPINNING ANTIBIOTIC MEDIATED DISRUPTION OF PULMONARY IMMUNE RESPONSES

抗生素被用来杀死引起有害感染的危险细菌菌株，但经常被不适当地开给那些主要原因是炎症而不是细菌感染的疾病。这包括哮喘，据信是由免疫系统驱动的某种类型的炎症引起的，称为2型炎症。动物模型的研究表明，通常生活在肠道和肺等组织中的无害细菌有利于健康的免疫系统，并可以保护肺部免受有害的2型炎症。其中许多无害的细菌也会被抗生素杀死，越来越多的动物模型实验证据表明，抗生素实际上会导致肺部的II型炎症，从而导致哮喘等疾病。到目前为止，还没有直接在人类身上研究抗生素对肺部免疫反应的影响的研究。然而，在生命早期服用多个疗程抗生素的人更有可能患上哮喘。我们的初步数据表明，在动物模型中使用抗生素可以改变肺部的免疫反应，特别是通过激活参与2型炎症的免疫细胞。目前项目的目的是研究口服抗生素是否对人类有类似的影响。我们将首先调查抗生素是否会导致健康人的肺部出现异常的免疫反应。我们将从肺部本身区分不同类型的免疫细胞，通过观察血液中的免疫细胞，我们将能够看到身体其他部分可能受到的影响。我们将确定免疫系统的任何变化是否与抗生素引起的肠道和肺部无害细菌种群的变化相对应。接下来，我们将调查抗生素是否会改变已经患有肺2型炎症的哮喘患者的免疫反应。我们将专注于发现参与抗生素驱动的免疫反应变化的细胞、分子和途径。这项工作旨在揭示可用于抵消抗生素有害副作用的新策略。这些新的途径还有可能形成对哮喘等2型炎症性疾病的更有针对性的治疗，并增加我们对无害的“友好”细菌如何帮助控制肺部免疫反应的总体理解。

Antibiotics are used to kill dangerous strains of bacteria that cause harmful infections, but are often inappropriately prescribed for diseases in which inflammation rather than a bacterial infection is the main cause. This includes asthma which is believed to be caused by a certain type of inflammation, driven by the immune system, called type 2 inflammation. Work in animal models shows that the harmless bacteria which normally live in tissues such as the gut and the lung are beneficial for a healthy immune system and can protect against harmful type 2 inflammation in the lung. Many of these harmless bacteria are also killed by antibiotics and there is increasing experimental evidence in animal models showing that antibiotics can in fact predispose to type 2 inflammation in the lung, contributing to conditions such as asthma. To date, there have been no studies in humans directly investigating the effects of antibiotics on immune responses in the lung. However individuals who have taken multiple courses of antibiotics earlier in life are more likely to develop asthma. Our pilot data indicate that antibiotic use in animal models alters immune responses in the lung, specifically by activating the immune cells involved in type 2 inflammation. The aim of the current project is to study whether oral antibiotic use has similar effects in humans. We will first investigate whether antibiotics causes healthy individuals to have abnormal immune responses in the lung. We will characterise different types of immune cells from the lungs themselves, and by looking at immune cells in the bloodstream, we will be able to see how the rest of the body may be affected. We will determine whether any changes to the immune system correspond to antibiotic induced changes in populations of harmless bacteria in the gut and the lung. Next, we will investigate whether antibiotics alter immune responses in asthmatic individuals who already have type 2 inflammation in the lung. We will focus on discovering cells, molecules and pathways that are involved in antibiotic-driven alterations of immune responses. This work aims to reveal new strategies that could be used to counteract the harmful side effects of antibiotics. These new pathways also have the potential to shape more targeted treatment in type 2 inflammatory diseases such as asthma, as well as increasing our general understanding of how harmless "friendly" bacteria help control immune responses in the lung.